Hepatocyte nuclear factor-1? regulates Wnt signaling through genome-wide competition with ?-catenin/lymphoid enhancer binding factor.

ABSTRACT: Hepatocyte nuclear factor-1? (HNF-1?) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1? produce cystic kidney disease, a phenotype associated with deregulation of canonical (?-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1? in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43 Levels of ?-catenin and expression of Wnt target genes are also increased in HNF-1? mutant mouse kidneys. Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in wild-type and mutant cells showed that ablation of HNF-1? increases by 6-fold the number of sites on chromatin that are occupied by ?-catenin. Remarkably, 50% of the sites that are occupied by ?-catenin in HNF-1? mutant cells colocalize with HNF-1?-occupied sites in wild-type cells, indicating widespread reciprocal binding. We found that the Wnt target genes Ccdc80 and Rnf43 contain a composite DNA element comprising a ?-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1? half-site. HNF-1? and ?-catenin/LEF compete for binding to this element, and thereby HNF-1? inhibits ?-catenin-dependent transcription. Collectively, these studies reveal a mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of ?-catenin/LEF chromatin binding.

SUBMITTER: Chan SC 

PROVIDER: S-EPMC6883834 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature